Immune modulation within the brain: recruitment of inflammatory cells and increased major histocompatibility antigen expression following intracerebral injection of interferon-γ

Sethna, Michael P.; Lampson, Lois A.

doi:10.1016/0165-5728(91)90121-m

Cited by 122 publications

(58 citation statements)

References 37 publications

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“…IL-2 produced from the brain tumors can enhance the activity of cytotoxic effector cells that are activated in peripheral tissues. 24,25 Immunohistochemical analysis also revealed that the migration of T cells and monocytes/macrophages into 9L/IL-2 brain tumors increased more significantly in the rats that were concurrently inoculated s.c. with 9L/IL-2 cells than in naive rats. The infiltration reached almost the same level as that observed in s.c. 9L/IL-2 tumors that were eventually rejected.…”

Section: Discussionmentioning

confidence: 97%

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Immunological responsiveness to interleukin-2-producing brain tumors can be restored by concurrent subcutaneous transplantation of the same tumors

et al. 2000

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The central nervous system shows tolerance for activated host immune reactions, and this relative unresponsiveness may lessen the efficacy of an immunotherapy for brain tumors. Using interleukin-2 (IL-2)-producing 9L rat gliosarcoma cells (9L/IL-2), we examined whether secretion of IL-2 from subcutaneous (s.c.) and/or intracerebral (i.c.) tumors can elicit augmented immunological responses to brain tumors. Syngeneic rats could reject 9L/IL-2 cells inoculated s.c., but developed 9L/IL-2 brain tumors by i.c. inoculation. The growth of i.c. 9L/IL-2 tumors was, however, significantly retarded compared with that of i.c. wild-type tumors. The growth of i.c. wild-type tumors was significantly suppressed when the rats concurrently received 9L/IL-2 cells s.c. Moreover, most of the rats that were inoculated i.c. with 9L/IL-2 cells did not develop brain tumors when concurrently injected s.c. with 9L/IL-2 cells. Immunohistochemical analysis on i.c. 9L/IL-2 tumors, when the rats were concurrently inoculated s.c. with 9L/IL-2 cells, revealed that migration of CD4 ϩ or CD8 ϩ T cells, monocytes/microglias, and macrophages was markedly augmented to a similar level as found in the s.c. 9L/IL-2 tumors. These results showed that systemic immune responses to brain tumor were induced in an immunologically privileged site by concurrent s.c. inoculation of the same tumors that produce IL-2. The present study may also raise the possibility of a therapeutic strategy for brain tumors by the combinatory expression of IL-2 gene using s.c. immunization followed by direct gene transfer into brain tumors.

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Section: Discussionmentioning

confidence: 97%

“…secretion of IL-2. 8, 24 Tjuvajev et al 8 reported that the rats with IL-2-secreting brain tumors died of severe brain edema despite induced antitumoral immunity, whereas other authors showed prolonged survival of animals treated with an i.c. injection of IL-2-secreting cells.…”

Section: Discussionmentioning

confidence: 99%

Immunological responsiveness to interleukin-2-producing brain tumors can be restored by concurrent subcutaneous transplantation of the same tumors

et al. 2000

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“…As a further experimental control over IFN-␥ expression, we administered AdIFN␥ to the CNS of GKO mice, which have no endogenous IFN-␥ expression. Other studies that have applied IFN-␥ to mouse CNS, either by transgenic expression or direct injection into CNS parenchyma (8,9,(11)(12)(13), or intrathecal injection of a viral vector encoding IFN-␥ to WT mice (15), did not include analysis of chemokine expression in the CNS. Our findings show that IFN-␥ induced a selective chemokine response.…”

Section: Discussionmentioning

confidence: 99%

“…IFN-␥ is a prototypic proinflammatory cytokine that can induce cascades of cytokine and chemokine expression. Although deleterious effects have been associated with its administration to an otherwise unmanipulated CNS by direct injection (8,9), or by transgenic expression (10 -13), there is compelling evidence that it has a protective effect during CNS inflammation. Intracerebroventricular injection of recombinant, or intrathecally administered virus-encoded IFN-␥ suppressed the onset of EAE (14,15), and depletion of IFN-␥ with anti-IFN-␥ Abs exacerbated EAE (16 -18) and rendered resistant mouse strains susceptible (19).…”

Section: Ifn-␥-induced Chemokines Synergize With Pertussis Toxin To Pmentioning

confidence: 99%

IFN-γ-Induced Chemokines Synergize with Pertussis Toxin to Promote T Cell Entry to the Central Nervous System

Millward

Caruso

Campbell

et al. 2007

The Journal of Immunology

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Inflammation of the CNS, which occurs during multiple sclerosis and experimental autoimmune encephalomyelitis, is characterized by increased levels of IFN-γ, a cytokine not normally expressed in the CNS. To investigate the role of IFN-γ in CNS, we used intrathecal injection of a replication-defective adenovirus encoding murine IFN-γ (AdIFNγ) to IFN-γ-deficient (GKO) mice. This method resulted in stable, long-lived expression of IFN-γ that could be detected in cerebrospinal fluid using ELISA and Luminex bead immunoassay. IFN-γ induced expression in the CNS of message and protein for the chemokines CXCL10 and CCL5, to levels comparable to those seen during experimental autoimmune encephalomyelitis. Other chemokines (CXCL2, CCL2, CCL3) were not induced. Mice lacking the IFN-γR showed no response, and a control viral vector did not induce chemokine expression. Chemokine expression was predominantly localized to meningeal and ependymal cells, and was also seen in astrocytes and microglia. IFN-γ-induced chemokine expression did not lead to inflammation. However, when pertussis toxin was given i.p. to mice infected with the IFN-γ vector, there was a dramatic increase in the number of T lymphocytes detected in the CNS by flow cytometry. This increase in blood-derived immune cells in the CNS did not occur with pertussis toxin alone, and did not manifest as histologically detectable inflammatory pathology. These results show that IFN-γ induces a characteristic glial chemokine response that by itself is insufficient to promote inflammation, and that IFN-γ-induced CNS chemoattractant signals can synergize with a peripheral infectious stimulus to drive T cell entry into the CNS.

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“…Dendritic cells also play a part in antigen presentation within CNS, as demonstrated by primate studies of experimental allergic encephalomyelitis (EAE) [7]. Immune modulation within the brain with upregulation of MHC antigens takes place at sites of injury and after exposure to cytokines [8]. There is experimental evidence that human glioma cells express CD 95 and Fas ligand, which enables them to interact with T cells and initiate apoptosis [9,10].…”

Section: Immune System and The Cnsmentioning

confidence: 99%

Current Immunotherapeutic Strategies for Central Nervous System Tumors

Kushen¹,

Sonabend²,

Lesniak³

2007

Surgical Oncology Clinics of North America

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Immunotherapy has emerged as a promising tool in the management of malignant central nervous system (CNS) tumors. Despite the improvement in patient survival, traditional approaches -which consist mostly of surgery, radiotherapy, and chemotherapy -have been largely unsuccessful in permanently controlling these aggressive tumors. Immunotherapeutic strategies therefore offer not only a novel approach, but also an advantage in a way other modalities have been failing. Specifically, the capabilities of the immune system to recognize altered cells while leaving normal cells intact offer tremendous advantage over the conventional therapeutic approaches. This review summarizes our current understanding of immunotherapeutic treatment modalities employed in clinical trials for management of malignant CNS tumors. Keywordsclinical trials; glioma; glioblastoma; immunotherapy; dendritic cells; cytokines; toxins Immune system and the CNSThe immune system has the ability to recognize and destroy foreign cells via two separate modalities: innate and adaptive immunity. The innate component consists of macrophages, natural killer (NK) cells, monocytes, and granulocytes. These cells identify molecular patterns involved in cellular transformation and release various cytokines and inflammatory mediators. The innate response lacks the memory capability for foreign antigens, a feature present in adaptive immune response. This latter component of immune system also features specificity for foreign antigens, imparted by presence of receptors on lymphocytes. Antigen presenting cells (APCs) also play a role in the adaptive response -they engulf foreign antigens and present them to the lymphocytes in the context of major histocompatibility complex. CD4+ T cells Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Recent advances in research on antigen presentation, specific cytokines, and T-cell cytotoxicity have given new direction to immunotherapeutic strategies against CNS tumors. Evidence of CNS manifestations after peripheral vaccination with brain-specific antigens in EAE and paraneoplastic cerebellar degeneration models have also lead to a search for possible immunotherapy regimens for management of malignant gliomas [32]. Current directions in immunotherapy investigations include the use of various cytokines, dendritic cells, viral and peptide vaccines, and toxins. NIH Public Access CytokinesCytokines augment T cell activation and MHC antigen expression. Antitumor effects mediated by expression of cytokines in cancer models have been demonstrated with IL-2, IL-4, IL-12, IL-23, IFN-α, and ...

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Immune modulation within the brain: recruitment of inflammatory cells and increased major histocompatibility antigen expression following intracerebral injection of interferon-γ

Cited by 122 publications

References 37 publications

Immunological responsiveness to interleukin-2-producing brain tumors can be restored by concurrent subcutaneous transplantation of the same tumors

Immunological responsiveness to interleukin-2-producing brain tumors can be restored by concurrent subcutaneous transplantation of the same tumors

IFN-γ-Induced Chemokines Synergize with Pertussis Toxin to Promote T Cell Entry to the Central Nervous System

Current Immunotherapeutic Strategies for Central Nervous System Tumors

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